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From 2 July 2013, all active substances manufactured outside of the European Union (EU) and imported into the EU must be accompanied by a written confirmation from the competent authority of the exporting country confirming that the standards of good manufacturing practice (GMP) and control of the manufacturing plant are equivalent to those in the EU.

These requirements constitute one of the main areas of change of the new European falsified medicines directive, which came into force in January 2013. They provide a clear legal basis for the concept of international cooperation on active substances (also known as active pharmaceutical ingredients or APIs) which is based on sharing responsibilities with local regulators.

The written confirmation is required per manufacturing site and per active substance and should provide the following assurances:

standards of GMP applicable at the plant are at least equivalent to those in force in the EU;

the plant is subject to regular and strict controls and effective enforcement of GMP, including inspections;

information on findings relating to non-compliance is supplied by the exporting third country without delay to the authorities in the importing country in the EU.

The duration of validity of the written confirmation is established by the exporting non-EU country.

These new requirements reinforce the need for pharmaceutical companies to ensure that the active substance manufacturers they are working with are registered with their respective local authorities and subject to adequate regulatory oversight, no matter where in the world they are located. Marketing-authorisation holders and applicants should always bear this in mind when selecting active substance suppliers to avoid future supply problems.

List of equivalent countries

The directive foresees that exporting countries with a regulatory framework equivalent to that of the EU will not need to issue written confirmations. Following a request from a non-EU country, the European Commission, together with GMP experts from Member States and with the support of the European Medicines Agency, will assess the regulatory framework of the requesters and if the assessment if positive, the county will be listed as an ‘equivalent country’.

Four countries have been listed so far by the European Commission: Australia, Japan, Switzerland and the United States.

An equivalence assessment is ongoing for Brazil. Israel and Singapore have requested to be listed as ‘equivalent countries’. The European Commission maintains a webpage on quality of medicines and GMP detailing the status of the requests received.

Inspections carried out in exceptional cases

In order to avoid the risk of shortages of medicines if the required written confirmation cannot be obtained, the directive provides for a waiver from the written confirmation in exceptional cases. The waiver can be used where an inspection by an authority of the European Economic Area (EEA) has been carried out with a positive outcome and the issue of a GMP certificate.

With around 30% of centrally authorised medicines using active substances that are sourced from third countries, the Agency has performed a risk analysis for centrally authorised products to identify priorities for inspections.The methodology was shared with Member States allowing them to apply a similar approach to nationally authorised medicines. The Agency is constantly monitoring the situation in liaison with Member States in order to coordinate this activity.

In the meantime, guidance for importers and national authorities has been prepared to deal with cases where active substances arrive in the EEA without the necessary written confirmation.This has been prepared to facilitate a harmonised approach over the coming weeks.

About the Falsified Medicines Directive

In July 2011, the EU strengthened the protection of patients and consumers by adopting a new Directive on falsified medicines for human use.

The Directive aims to strengthen the supervision of the supply chain of medicinal products and active substances, in order to avoid falsified medicines entering the EU market.

In addition to the requirements related to active substances described above, the directive also foresees:

the introduction of unique identifiers printed or attached to every single pack of medicines subject to prescription and other medicines at risk of being falsified;

the construction of a unique database containing information on both GMP and good distribution practices (GDP): EudraGMDP was launched in April 2013;

the introduction of an obligatory logo that will be placed on the websites of legally operating online pharmacies.